ABSTRACT: Alzheimer?s disease and related disorders (ADRD) is a growing public health concern for American Indian and Alaska Native (AI/ANs) people, but AI/ANs are profoundly underrepresented in ADRD research. For example, the National Alzheimer?s Coordinating Center database, an important resource for influential ADRD studies, includes just 162 AI/ANs out of 31,000 adults (0.5%). This is a troubling exclusion, since AI/ANs have high burdens of many ADRD risk factors, including hypertension, type 2 diabetes, traumatic brain injury, vascular brain injury (VBI), and stroke. The Cerebrovascular Disease and its Consequences in American Indians (CDCAI) study, conducted by our research group, is the only prospective cohort study with longitudinal data for rigorous evaluation of cognitive function, ADRD, and VBI in any US Native population. In its first wave of exams, CDCAI collected data on 818 elderly AI/ANs living on reservations in 3 primarily rural, geographic regions; the second wave of exams is underway. CDCAI is yielding seminal findings on ADRD risk factors and biomarkers in AI/ANs; 33% of the sample showed evidence of VBI, with men even higher. Yet the cohort is not representative of the national AI/AN population because 72% of AI/ANs now reside in urban areas. Urban A/ANs represent an ?invisible tribe? that is largely absent from health research. One likely explanation is that urban environments feature distinctive risk and protective profiles, including lifestyle factors that exacerbate age-related cognitive decline, and protective factors such as better access to acute and specialty care and higher levels of education. Accordingly, we propose a novel study, URBan Native Elders (URBANE), to replicate CDCAI in a large cohort of urban AI/ANs with broad geographic representation. We will recruit 1,200 men and women ages 55 and older in 5 geographically diverse metropolitan areas with large AI/AN populations. Data collection will include MRI for all participants, and genetic testing for alleles associated with ADRD in the all-races population. We will expand CDCAI protocols to reflect state-of-the- art imaging and neuropsychological assessments. We will use protocols established by the CDCAI to estimate probable ADRD based on a single exam. The resulting analyses will establish the baseline prevalence of cognitive impairment, probable ADRD, and VBI and their associations with clinical, genetic, neuroimaging, behavioral, and lifestyle risk and protective factors. Of importance, this cross-sectional study will lay the foundation for future longitudinal research on ADRD. Our Specific Aims are to: Quantify the extent of probable ADRD and VBI as defined by brain MRI, and determine their associations with cognitive functioning in a diverse sample of urban AI/AN elders. 2) Evaluate associations between conventional risk factors and probable ADRD, and evaluate potential mediation of selected risk factors by VBI. 3) In an exploratory analysis, evaluate potential differences in our primary associations by sex; and evaluate education and access to healthcare as potential protective factors for cognitive impairment and probable ADRD in elders with VBI.